Formulation and Evaluation of Extended Release Ocular Inserts prepared from Synthetic and Natural Biodegradable - Biocompatible Polymers

 

Girish Pai K* and M. Sreenivasa Reddy 

Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India

 

ABSTRACT:

Objective of this research was to formulate and evaluate extended release ocular inserts/ films of anti-conjunctival drug, Sodium Cromoglycate. Novel natural polymer namely, Pullulan and synthetic polymer namely, Hydroxy Ethyl Cellulose (HEC) were used as biodegradable, biocompatible polymers. Standardized glass mould was used to prepare ocular inserts. The ocular inserts were prepared with constant drug content and 10% concentration of polymer. The aim was to maintain the thickness of ocular insert at not more than 0.40 mm. Ocular inserts were prepared using Pullulan 10% and HEC 10%. Formulated ocular inserts were evaluated for parameters like appearance, thickness, weight variation and uniformity of drug content. For in vitro studies, In-House (IH) vial method was used to determine the rate of dissolution using phosphate buffer saline (pH 7.4). Ocular inserts prepared from both polymers showed differences with respect to physical properties such as appearance, weight and thickness. Films of both the polymers showed differences with respect to physico-chemical properties such as appearance, weight and thickness. The films were smooth, thin, soft and pliable. Appearance of Pullulan 10% films was almost clear to slightly opaque whereas films of HEC 10% were slightly off white in color. The Pullulan 10% films had average thickness of 0.21mm and films of HEC 10% had average thickness of 0.19mm.The average weights of Pullulan 10% films were 10.8 mg whereas average weight of HEC 10% films was found to be 14.8 mg. The drug content of Pullulan 10% film and HEC 10% film was confirming to limits. The in vitro release study was carried out using phosphate buffer saline of pH 7.4. Both the films dissolved completely over a period of time. Pullulan 10% films showed in vitro release for 3 hours whereas HEC 10% films showed in vitro release for 6 hours. However, since the thickness of Pullulan 10% films are well within required specification of less than 0.40 mm, further studies shall be carried out with Pullulan by increasing the concentration and shall then evaluated for thickness and in vitro release studies. We assume that higher concentration of Pullulan films can extend the drug release for few more hours thus yielding promising result.

 

 

INTRODUCTION:

Eye is a sensitive organ of vision and a challenging subject for topical administration of drugs. A major goal of pharmacotherapeutics is the attainment of an effective drug concentration at the intended site of action for a desired period of time¹. It was decided to formulate and evaluate Sodium cromoglycate extended release ocular inserts for allergic conjunctivitis. Conjunctivitis is also known as Pink eye. The condition is mainly due to infection or an allergic reaction. Signs and symptoms include red eye, irritation and watering.

 

Ophthalmic preparations are sterile products essentially free from foreign particles suitably formulated and packed for either topical application to eyelids or instillation into the space between eyeball and eyelids (on cul-de-sac).

 

Limitations of conventional ophthalmic preparations¹:

i) Eye drops (Solutions and suspensions)

A great part of the medicament is immediately diluted in tear film, frequent instillation of eye drops also becomes necessary in order to maintain a sustained level of medication, Subsequent absorption of this drained drug may result in some undesirable doses of medication and it may cause irritation and patient inconvenience.

 

ii) Ointments

Blurring of vision is a major drawback, Frequency of administration is not reduced markedly and Do not yield a constant drug bioavailability as predicted.

In order to eliminate the constraints placed by the conventional ocular therapy namely short residence time, large drainage factor imposed by the eye, frequent instillation, patient inconvenience, lacks delayed action etc, an attempt is being made in the current study to develop, evaluate and optimize a stable extended release ocular insert which would provide following important benefits to patients.

·        Controlled release of medicament, enhanced patient compliance, therapeutic efficacy, reduced dosage regimen and targeted drug delivery etc.

 

This approach will avoid the frequent instillation of Sodium cromoglycate eye drops in the management of various types of conjunctivitis. The concentration of drug in the extended release ocular insert can also be phenomenally reduced (as compared to eye drops) with increased rate of absorption.

Chemically, Sodium cromoglycate is disodium 4,4’-dioxo-5,5’-(-2-hydroxy trimethylene dioxy) di (chromene -2-carboxylate) with a molecular weight of 512.3. Its molecular formula is C₂₃H₁₄Na₂O_11. The drug is official in pharmacopoeias like IP, BP, and USP².

 

Sodium cromoglycate is an anti-allergic agent and a mast cell stabilizer that acts mainly by inhibiting the release of inflammatory mediators and autocoids from mast cells.

 

Figure: 1 (Chemical structure of Sodium cromoglycate)

 

Two polymers were used to prepare ocular films. A novel natural polymer, Pullulan and synthetic polymer namely, Hydroxy ethyl cellulose (HEC) were used. Pullulan is a water-soluble neutral polysaccharide produced from starch syrup by fermentation. Available as a white powder, it is essentially odorless, flavorless, and stable⁴. The good binding and film-forming properties of Pullulan make it a valuable ingredient for coating tablet. Pullulan can also be used to make non-animal capsules and has the same exceptional oxygen barrier function as the film. Pullulan is listed on the USP-NF (United States Pharmacopoeia-National Formulary) and JP (Japanese Pharmacopoeia). On the other hand, HEC is partially substituted 2-hydroxyethyl ether of cellulose. It is white, odorless, tasteless, free flowing powder softens at 137ºC. Pharmaceutically it is used as a thickener, binder, suspending agent in lotions and ophthalmic solutions³.

 

MATERIALS AND METHODS:

Materials:

a.     Chemicals: Sodium cromoglycate (Marck biosciences ltd), Pullulan (TCI Japan), Hydroxyethylcellulose (Colorcon India), Di-sodium hydrogen orthophosphate, Potassium dihydrogen orthophosphate and Sodium chloride.

 

b.    Instruments/Equipment: Mini Tray dryer, Glass mould, IH fabricated die punch set, UV Visible spectrophotometer, Electronic weighing balance, Calibrated pH meter (EUTECH pH 510), Remi stirrer and Vernier calipers (Mitutoyo, Japan).

 

Methods:

Method development:

Sodium cromoglycate is official in Pharmacopoeia’s like IP, BP and USP. Indian Pharmacopoeial method was adopted and standard plot of Sodium cromoglycate was carried out using Phosphate buffer of pH 7.4².

 

Figure: 2 (Standard plot of Sodium cromoglycate)

 

Preparation, standardization of glass mould and In House fabrication of SS punch die set to cut ocular films:

In-House fabricated mould made of Glass was standardized and used. Each mould was standardized and calculated for number of films that can be prepared for each batch using a particular coded mould. Inhouse designed punch die set was locally fabricated made of stainless steel (Grade – SS 316) punch to size uniform oval shaped ocular films of dimension 8 mm x 5 mm. Glass mould, punch die set and oval ocular film is represented below. (The oval shaped film is shown in picture 3 on the extreme right side).

   

Figure: 3 (In-House fabricated glass mould and punch die set and a ocular film of oval shape is shown in extreme right side)

 

 

Dose calculation:

6 mg of Sodium cromoglycate was included in each extended release ocular film.

 

Formulation of extended release ocular inserts:

Accurately weighed amount of polymer was taken and dispersed in known quantity of water for hydration (few minutes) and this was stirred using remi stirrer at 2500 rpm for 25 to 30 minutes for uniform dispersion. Accurately weighed required amount of drug (for each mould) was added to above viscous solution and stirred at 2500 rpm for about 10 minutes. PEG 400 (5%w/w) was added as plasticizer and mixed well for uniformity. The resultant mass was poured into a glass mould and dried in lab scale tray drier at 50º C for 4 hours. The dried film was removed carefully and cutting was done using punch die set.

 

Composition of polymers and plasticizers in formulations:

Formulation code	Polymer and concentration	Plasticizer*	Drug content in each insert
FC 1	Pullulan 10% w/v	PEG 400	6 mg
FC 2	HEC 10% w/v	PEG 400	6 mg

*Based on polymer weight

 

Evaluation of ocular inserts: ^5,6

The extended release ocular insert was evaluated for various physico-chemical tests like Appearance or description, thickness, weight variation, drug content and in vitro drug release (IH method) studies.

 

RESULTS AND DISCUSSION:

The ocular films were prepared using two different polymers, Pullulan 10% and HEC 10%. Films of both the polymers showed differences with respect to physic-chemical properties such as appearance, weight and thickness. The films were smooth, thin, soft and pliable. Appearance of Pullulan 10% films was almost clear to slightly opaque whereas films of   HEC 10%  were slightly off white in color.

 

The thickness was within acceptable limits at not more than 0.40mm. The Pullulan 10% films had average thickness of 0.21mm and films of HEC 10% had average thickness of 0.19mm.

The average weights of Pullulan 10% films were 10.8 mg whereas average weight of HEC 10% films was found to be 14.8 mg.

 

The drug content or assay of each film complied as per predetermined specification. The drug content of Pullulan 10% film was found to be 6.1mg and that of HEC 10% film was found to be 5.98mg.

 

The in vitro release study was carried out using phosphate buffer saline of pH 7.4. Both the films dissolved completely over a period of time. Pullulan 10% films showed in vitro release for 3 hours whereas HEC 10% films showed in vitro release for 6 hours. On storage at NMT 25ºC for 4 weeks, both films remained stable and no changes were found in appearance and drug content.

 

Time in minutes	Pullulan 10% CPDR
0	0
30	36.1
60	42.9
90	51.1
120	63.8
150	79.3
180	95.6

[CPDR- Cumulative percent drug release]

\

Figure: 4 (In vitro release from 10% Pullulan films)

 

Time in minutes	HEC 10% CPDR
0	0
30	40.8
60	64.6
90	69.7
120	73.4
150	78.1
180	80.2
210	81.1
240	84.6
270	91.8
300	95
330	95.8
360	98.3

[CPDR- Cumulative percent drug release]

 

Figure: 5 (In vitro release from 10% HEC films)

 

CONCLUSION:

Ocular films prepared with Pullulan 10% and HEC 10% were biodegradable. The thickness of Pullulan 10% films was found to be higher than HEC 10% films, but film weight was more in case of HEC films. Out of the two ocular films, HEC 10% films were better when compared to Pullulan 10% films especially with respect to in vitro release studies. However, since the thickness of Pullulan 10% films are well within required specification of less than 0.40 mm, further studies shall be carried out with Pullulan by increasing the concentration and shall then be evaluated for thickness and in vitro release studies. We assume that higher concentration of Pullulan films can extend the drug release for few more hours thus yielding promising result. The above work was interesting and challenging. The systematic extension of this work may yield good results which would be more effective and overcome the drawbacks of conventional Sodium cromoglycate eye drops. The final optimized formulation shall be subjected for stability studies as well as in vivo studies using albino rabbits.

 

REFERENCES:

1.       Chien Yie W., Ocular Controlled Release Drug Administration. In: Novel Drug Delivery Systems. 1^st Ed. New York: Marcel Dekker Inc; 1982.

2.       Sodium cromoglycate – Monograph, Indian Pharmacopoeia, 2007, 5^th ed., Vol 3, 1715-1717.

3.       Handbook of Pharmaceutical Excipients. Vol. I. American Pharmaceutical Association and the Pharmaceutical Association of Great Britain, pp. 131. 1986.

4.       http://www.intl.hayashibara.co.jp/products.php?jpml=products_pharmaceuticals_pullulan. Accessed on 15/06/2013.

5.       Sankar, V., Chandrasekaran, A.K., Durga, S., Geetha, G., Ravichandran, V., Vijayakumar, A., Raguraman, S. Design and Evaluation of Diclofenac Sodium Ophthalmic Inserts. Acta Pharm. Sci. 2006. 48, 5-10.

6.      Deepak Nautiyal, Vikram Singh, Sahadat Ali. Formulation and Evaluation of Sustained Release of Ofloxacin Ocular Inserts. Research J. Pharm. and Tech. 2012. 5 (12). pp. 1497-1499.

 

 

 

Received on 29.10.2013       Modified on 10.11.2013

Accepted on 22.11.2013      © RJPT All right reserved